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Journal of Clinical Oncology, Vol 20, Issue 15 (August), 2002: 3249-3253
© 2002 American Society for Clinical Oncology

Phase I Study of Temozolomide in Relapsed/Refractory Acute Leukemia

By Karen Seiter, Delong Liu, Thomas Loughran, Ahmad Siddiqui, Paul Baskind, Tauseef Ahmed

From the Zalmen A. Arlin Cancer Institute and Department of Medicine, New York Medical College, Valhalla, NY.

Address reprint requests to Karen Seiter, MD, Room 250, Munger Pavilion, New York Medical College, Valhalla, NY 10595; email: karen_seiter{at}nymc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To determine the dose-limiting toxicity and maximum-tolerated dose of temozolomide in patients with acute leukemia.

PATIENTS AND METHODS: Twenty patients (16 with acute myelogenous leukemia, two with acute lymphoblastic leukemia, and two with chronic myelogenous leukemia in blastic phase) received 43 cycles of temozolomide. Patients began treatment at two different dose levels: 200 mg/m2/d for 7 days or 200 mg/m2/d for 9 days.

RESULTS: Prolonged aplasia was the dose-limiting toxicity, and the maximum-tolerated dose was 7 days of temozolomide. Overall treatment was well tolerated: hospitalization was required in only nine of 43 courses, and there were no treatment-related deaths. Two patients obtained a complete response, and two others met criteria for complete response except for platelet recovery. Overall, nine of 20 patients had a significant decrease in bone marrow blasts after temozolomide treatment.

CONCLUSION: Temozolomide was well tolerated and had significant antileukemic activity when administered as a single agent. Further studies of temozolomide in hematologic malignancies are indicated.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
STANDARD ANTHRACYCLINE- and cytarabine-based chemotherapy regimens yield complete remissions in most patients with acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL); however, long-term remissions occur in only 25% of patients.1,2 Patients with chronic myelogenous leukemia in blastic phase (CML-BP) have a particularly poor prognosis and often do not respond to standard chemotherapy regimens. The development of newer classes of chemotherapeutic agents is needed in these diseases.

Temozolomide is a second-generation oral alkylating agent that is currently approved for the treatment of patients with refractory anaplastic astrocytoma.3,4 In these patients, the standard dose of temozolomide is 200 mg/m2/d for 5 days. Temozolomide is an analog of dacarbazine (DTIC), both of which are prodrugs of the active agent triazene 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC). However, unlike DTIC, which requires enzymatic activation in the liver, temozolomide undergoes spontaneous conversion to MTIC at physiologic pH.5 Early laboratory studies demonstrated that DTIC has activity against L1210 leukemia cell lines.6 It is interesting to note that the leukemia cells developed altered antigenicity after treatment with DTIC in a process known as chemical xenogenization.7 Several preclinical studies have also demonstrated the activity of temozolomide against the leukemia cell lines U-937, L1210, and P388.8 Despite this, there have been few trials of DTIC and no clinical trials of temozolomide in patients with leukemia. In one small study, four of nine patients with AML had a significant decrease in blasts after treatment with DTIC.9 In that study, in vitro sensitivity to temozolomide was seen in the leukemic blasts of patients who responded clinically to DTIC.

On the basis of the in vitro data demonstrating sensitivity of temozolomide to both leukemia cell lines, as well as blasts from patients, and the clinical response to DTIC in leukemia patients, we conducted a phase I study of temozolomide in patients with relapsed and refractory acute leukemia. Preclinical data demonstrated that the effects of temozolomide were schedule dependent, with greater efficacy noted with repetitive divided-dose administration compared with a single bolus administration.5 Thus, we chose to increase the dose of temozolomide by increasing the total number of days of drug administration.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection
Adult patients with histologically confirmed AML, ALL, or CML-BP were eligible for this study. Patients with AML or ALL must have either relapsed from or been refractory to standard therapy. No prior treatment was required for patients with CML-BP. Other eligibility criteria included Eastern Cooperative Oncology Group performance status <= 2, serum bilirubin <= 1.5 mg/dL, and serum creatinine <= 2.0 mg/dL. Patients must have had no antileukemic therapy (except hydroxyurea) in the 4 weeks before study entry and must have recovered from the toxicity of the prior therapy. All patients gave written informed consent as approved by the institutional review board of New York Medical College.

The pretreatment evaluation included a complete history and physical examination, complete blood count, chemistry profile, and coagulation profile. Bone marrow aspiration and biopsy were obtained for histochemical staining, cytogenetics, and flow cytometric analysis of cell-surface markers.

Treatment Plan
All patients received temozolomide 200 mg/m2/d as a single oral dose on an empty stomach. Dose escalation was accomplished by increasing the number of days of treatment per cycle. The first cohort of patients was treated with temozolomide for 7 days per cycle. The second cohort received 9 days of treatment per cycle. At least three new patients were entered at each dose level. The maximum-tolerated dose (MTD) was defined as the dose level below that which induced dose-limiting toxicities. If two of six patients developed grade 3/4 nonhematologic toxicity, this level was considered above the MTD. If no more than one patient developed grade 3 toxicity at the next lower dose level, this level was considered the MTD. Hematologic toxicity was considered dose limiting only if prolonged, severe aplasia (absolute neutrophil count <= 500/mm3 and platelet count <= 20,000/mm3) occurred in the absence of disease progression. The decision to escalate subsequent patients to a higher dose level was based on first-cycle toxicity. Patients with evidence of either a formal response to therapy or clinical benefit in the absence of a formal response were eligible to receive subsequent courses of temozolomide after recovery from the previous cycle. Treatment continued until there was evidence of disease progression or intolerable toxicity. Patients with significant toxicity during any cycle received subsequent courses of therapy with a reduced number of days of temozolomide.

Patients received prophylactic antiemetics consisting of granisetron 1 mg orally daily during temozolomide. Neutropenic patients also received prophylactic antibiotics consisting of ciprofloxacin, acyclovir, and either fluconazole or itraconazole. Febrile patients were treated with standard broad-spectrum intravenous antibiotics.

Evaluations
During induction, complete blood counts and chemistry profiles were obtained twice a week or more, as clinically indicated. Bone marrow aspiration and biopsy were performed before treatment, at day 28, and then at the time of peripheral count recovery. Subsequent bone marrows were obtained every 3 months until disease progression. Toxicity was graded according to the National Cancer Institute common toxicity criteria.10

Response Criteria
A complete remission required a peripheral blood neutrophil count of more than 1,000/mm3, a platelet count of more than 100,000/mm3, a normocellular marrow with less than 5% blasts, and the absence of extramedullary leukemia. All criteria must have been present for at least 4 weeks. Patients with all of the criteria except for not obtaining a platelet count of more than 100,000/mm3 were classified as in complete remission except for platelets (CRp) provided that they were platelet transfusion independent and met all criteria for at least 4 weeks. All other patients were classified as treatment failures.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients
Twenty patients received 43 cycles of temozolomide at two different dose levels (Table 1). The baseline characteristics of the patients are listed in Table 2. Sixteen patients had AML, two had ALL, and two had CML-BP. The median age was 44 years (range, 21 to 79 years). Eight patients had AML that arose out of myelodysplastic syndrome. Five patients had normal cytogenetics, and 15 had poor-risk cytogenetics. The median number of prior induction regimens was two (range, one to six regimens). Five patients had relapsed after bone marrow or stem-cell transplantation (matched unrelated donor, n = 4 [two ablative, two nonmyeloablative]; autologous, n = 1).


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  		Table 1. Temozolomide Dose Levels
 

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  		Table 2. Baseline Characteristics (N = 20)
 
Hematologic Toxicity and Hospitalization
Prolonged aplasia was the dose-limiting toxicity. Patients treated with 9 days of temozolomide were unable to receive a second course of temozolomide for a median of 60 days (range, 47 to 74 days), compared with a median of 39 days for patients receiving 7 days of temozolomide (range, 34 to 69 days). Therefore, the MTD of temozolomide was 200 mg/m2/d for 7 days. As expected, most patients had significant blood count abnormalities at the time of entry into this study. For patients treated with 7 days of temozolomide, the median nadir WBC was 700/mm3 (range, 200 to 9,100/mm3) and occurred at a median of 12 days (range, 3 to 28 days) after the start of treatment. These patients required a median of two packed RBC transfusions (range, zero to 14) and two platelet transfusions (range, zero to 22) during cycle 1. Three of 11 patients required no RBC transfusions, and two patients did not require platelet transfusions. For patients treated with 9 days of temozolomide, the median nadir WBC was 500/mm3 (range, 200 to 12,000/mm3) and occurred at a median of 19 days (range, 7 to 35 days) after the initiation of temozolomide. These patients required a median of two RBC transfusions (range, zero to 13) and four platelet transfusions (range, zero to 14) during cycle 1. Two of nine patients required no RBC transfusion, and one patient did not require platelet transfusions. Most patients receiving subsequent courses received 5 days of temozolomide (Table 1). Hematologic toxicity was less marked in these patients. Two of the four responding patients required no transfusions during subsequent courses. A third patient required a single platelet transfusion during each subsequent course. The fourth responding patient required four platelet transfusions and two to five packed RBC transfusions during each subsequent course.

During induction, there were eight episodes of neutropenic fever that required hospitalization in seven cases. Five of these episodes occurred in patients receiving 7 days of temozolomide, and three occurred in patients receiving 9 days of treatment. There was only one episode of neutropenic fever in a patient receiving consolidation therapy. For those receiving intravenous antibiotics, the median number of antibiotic days was 13 (range, 3 to 52). One additional patient (who had relapsed after matched unrelated donor bone marrow transplantation) required hospitalization during the third course of temozolomide because of a hip fracture from avascular necrosis of the femoral head. The median duration of hospitalization (for those hospitalized) was 18 days (range, 4 to 55 days). Hospitalization was not required during 33 courses of therapy. There were no treatment-related deaths.

Nonhematologic Toxicity
Nonhematologic toxicity was more common in patients receiving 9 days of therapy; however, none of these toxicities was dose limiting. Five of nine patients receiving 9 days of therapy developed nausea, compared with one of 11 patients receiving 7 days of therapy. Vomiting occurred in three patients receiving 9 days of therapy, compared with one patient receiving 7 days of treatment. Two patients treated with 9 days of temozolomide developed significant headache. One patient treated with 7 days of temozolomide developed grade 4 confusion in the setting of neutropenic fever. Other grade 1 to 2 toxicities included constipation, dizziness, and fatigue. Mild increases of liver function tests (all grade 1 to 2) occurred in eight patients. In each case, the abnormalities resolved spontaneously and were not clinically significant.

Responses
Two patients achieved a complete remission, and two met all criteria for CRp. Five additional patients had a significant decrease in bone marrow blasts but did not meet criteria for a formal response (ie, a significant decrease in bone marrow blasts occurred in nine of 20 patients; Fig 1).



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  		Fig 1. Percentage of bone marrow blasts before and after treatment with temozolomide.

 
Of the patients with a formal complete response, one was a 68-year-old woman with AML with trisomy 11 in third relapse. The patient obtained a complete remission after one course of therapy and has remained in remission with temozolomide for 14 months. The second patient was a 42-year-old woman with precursor B-cell ALL and t(4;11) 1 year after treatment for stage II breast cancer. The patient relapsed shortly after matched unrelated donor bone marrow transplantation was performed in first remission. At the time of entry onto this study, the patient was not receiving immunosuppression, was without graft-versus-host disease, and had low-level leukemia in the bone marrow which was confirmed by morphology, flow cytometry, and cytogenetics. The patient had a complete response after one course of temozolomide and remained in remission with therapy for 9 months before her disease progressed. Two patients met criteria for CRp. One had AML with multiple poor-risk cytogenetics in second relapse after autologous transplantation. The patient obtained a CRp (highest platelet count, 45,000/mm3) after one course of therapy. The patient maintained this response with therapy for 10 months. The final patient was a 66-year-old woman with AML in second relapse with diploid cytogenetics. The patient achieved a CRp (highest platelet count, 83,000/mm3) after one course of therapy and continued on therapy for 11 months until her disease progressed.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Temozolomide is a second-generation alkylating agent with demonstrated activity against leukemia cell lines.3,8 In this study we demonstrated that temozolomide was well tolerated and had significant antileukemic activity in patients with acute leukemia. Most patients received treatment in the outpatient setting, and four of 20 patients treated had clinical responses with this single agent. In addition, nine of 20 patients treated had a significant decrease in bone marrow blasts after temozolomide treatment.

Several laboratory studies have evaluated the mechanism of action of temozolomide in leukemia cell lines and have suggested rational approaches to increase the effectiveness of this drug in patients with leukemia. Temozolomide converts spontaneously to MTIC at physiologic pH.5 MTIC dissociates into aminoimidazole carboxamide and a methyldiazonium ion, which methylates DNA. Although temozolomide methylates a variety of DNA sites, the cytotoxic activity of temozolomide correlates with the degree of methylation of O6-guanine.11 This methylation results in mispairing of guanine with thymine, and, in the presence of an active mismatch-repair pathway, results in DNA strand breaks and apoptosis.8,12

One obstacle to temozolomide cytotoxicity is the DNA repair enzyme O6-guanine DNA alkyltransferase (OGAT). OGAT removes from O6-guanine the methyl groups that would otherwise lead to apoptotic cell death.13 Because OGAT becomes irreversibly inactivated in this process, the degree to which a cell can repair itself is inversely proportional to the level of OGAT present. This has been demonstrated in several laboratory studies. For example, temozolomide is active against L1210, U-937, and K562, three cell lines with low levels of OGAT.14 However, when L1210 cells are transfected to express high levels of OGAT, they become resistant to temozolomide.15 In these cells, sensitivity to temozolomide is restored after the addition of O6-benzylguanine, a specific OGAT inhibitor.16 However, leukemia cell lines with high baseline levels of OGAT expression (Daudi, Jurkat, and HL-60) are relatively resistant to temozolomide.8 In the HL-60 and Daudi cell lines, sensitivity to temozolomide is restored by pretreatment exposure to O6-benzylguanine; however, Jurkat cells remain resistant because of defects in the required mismatch-repair pathway.

The importance of OGAT levels in the blasts of leukemia patients has also been demonstrated. In a pilot study of DTIC in patients with acute leukemia, Franchi et al9 found that low OGAT levels and leukemic blast sensitivity to temozolomide in vitro were found in four of nine patients who responded to in vivo treatment with DTIC. A follow-up study by this group indicated that OGAT levels varied widely among the leukemia blasts of different patients, with a mean value that was higher in ALL than in AML.17 Approximately 25% of leukemic blasts from patients with AML had low OGAT activity, and an inverse correlation was found between OGAT levels and leukemic blast sensitivity to temozolomide.

Because only 25% of leukemia cells demonstrate low levels of OGAT, strategies to deplete OGAT in these cells could potentially render them more sensitive to temozolomide. One strategy is to combine temozolomide with other agents, such as cisplatin, that deplete OGAT. Piccioni et al18 demonstrated that cisplatin and temozolomide were synergistic in leukemia cell lines and that in vivo treatment of leukemic patients with cisplatin was followed by a reduction of OGAT activity in peripheral blood mononuclear cells. D’Atri et al19 reported that, in Jurkat cells, cisplatin decreased OGAT activity in a time- and dose- dependent manner, with maximal suppression observed 24 hours after treatment with cisplatin. This reduction was thought to be due to decreased transcription of the OGAT gene. Temozolomide alone also depleted OGAT activity, with almost complete loss of activity occurring immediately after treatment with temozolomide. In this study, combinations of cisplatin and temozolomide caused substantial and prolonged OGAT depletion. Thus, cisplatin is potentially one agent that could increase the efficacy of temozolomide.

A specific way to decrease OGAT activity is through the use of inhibitors of the enzyme. O6-Benzylguanine is the inhibitor that has been most studied to date. Baer et al20 found that when O6-benzylguanine pretreatment was combined with repeated doses of temozolomide, a dramatic potentiation (300-fold) was seen in MAWI (human colorectal cancer) cells, which express high levels of OGAT. However, this effect was not demonstrated in a cell line expressing low levels of OGAT. In contrast, Wedge and Newlands21 reported that O6-benzylguanine enhanced the sensitivity to temozolomide of glioma xenografts with low OGAT activity, suggesting that this inhibitor could increase the efficacy of temozolomide even in tumors that are intrinsically sensitive to the drug. On the basis of these and other studies, clinical trials combining O6-benzylguanine with temozolomide are currently ongoing.

In conclusion, temozolomide is well tolerated and has significant activity in patients with acute leukemia. The recommended phase II single-agent dose is 200 mg/m2/d for 7 days as induction and 200 mg/m2/d for 5 days for postremission therapy. Studies of temozolomide in combination with other antileukemic agents, and studies that prospectively analyze OGAT levels, are indicated.


   ACKNOWLEDGMENTS
 
Supported by a grant from Schering-Plough Corp, Kenilworth, NJ.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Mayer RJ, Davis RB, Schiffer CA, et al: Intensive post-remission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 331: 896-903, 1994[Abstract/Free Full Text]

2. Weiss M, Maslak P, Feldman E, et al: Cytarabine with high-dose mitoxantrone induces rapid complete remission in adult acute lymphoblastic leukemia without the use of vincristine or prednisone. J Clin Oncol 14: 2480-2485, 1996[Abstract]

3. O’Reilly SM, Newlands ES, Glaser MG, et al: Temozolomide: A new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumors. Eur J Cancer 29A: 940-942, 1993[CrossRef][Medline]

4. Yung WK, Prados MD, Yaya-Tur R, et al: Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. J Clin Oncol 17: 2762-2771, 1999[Abstract/Free Full Text]

5. Stevens MF, Hickman JA, Langdon SP, et al: Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-D]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res 47: 5846-5852, 1987[Abstract/Free Full Text]

6. Venditti JM: Antitumor activity of DTIC (NSC-45388) in animals. Cancer Treat Rep 60: 135-140, 1976[Medline]

7. Bianchi R, Citti L, Beghetti R, et al: O6-Methylguanine-DNA methyltransferase activity and induction of novel immunogenicity in murine tumor cells treated with methylating agents. Cancer Chemother Pharmacol 29: 277-282, 1992[CrossRef][Medline]

8. Tentori L, Graziani G, Gilberti S, et al: Triazene compounds induce apoptosis in O6-alkylguanine-DNA alkyltransferase deficient leukemia cell lines. Leukemia 9: 1888-1895, 1995[Medline]

9. Franchi A, Papa G, D’Atri S, et al: Cytotoxic effects of dacarbazine in patients with acute myelogenous leukemia: A pilot study. Haematologica 77: 146-150, 1992[Medline]

10. National Cancer Institute: Guidelines for Reporting of Adverse Drug Reactions. Bethesda MD, Division of Cancer Treatment, National Cancer Institute, 1998

11. Denny BJ, Wheelhouse RT, Stevens MF, et al: NMR and molecular modeling investigation of the mechanism of activation of the antitumor drug temozolomide and its interaction with DNA. Biochemistry 33: 9045-9051, 1994[CrossRef][Medline]

12. Swann PF: Why do O6-alkylguanine and O4-alkylthymine miscode? The relationship between the structure of DNA containing O6-alkylguanine and O4-alkylthymine and the mutagenic properties of these bases. Mutat Res 233: 81-94, 1990[Medline]

13. Pegg AE: Repair of O6-alkylguanine by alkyltransferases. Mutat Res 462: 83-100, 2000[CrossRef][Medline]

14. Taverna P, Catapano CV, Citti L, et al: Influence of O6-methylguanine on DNA damage and cytotoxicity of temozolomide in L1210 mouse leukemia sensitive and resistant to chloroethylnitrosoureas. Anticancer Drugs 3: 401-405, 1992[Medline]

15. Graziani G, Faraoni I, Grohmann U, et al: O6-Alkylguanine-DNA alkyltransferase attenuates triazene-induced cytotoxicity and tumor cell immunogenicity in murine L1210 leukemia. Cancer Res 55: 6231-6236, 1995[Abstract/Free Full Text]

16. Tentori L, Orlando L, Lacal PM: Inhibition of O6-alkylguanine DNA-alkyltransferase or poly(ADP-ribose) polymerase increases susceptibility of leukemic cells to apoptosis induced by temozolomide. Mol Pharmacol 52: 249-258, 1997[Abstract/Free Full Text]

17. D’Atri S, Piccioni D, Castellano A, et al: Chemosensitivity to triazene compounds and O6-alkylguanine-DNA alkyltransferase levels: Studies with blasts of leukemic patients. Ann Oncol 6: 389-393, 1995[Abstract/Free Full Text]

18. Piccioni D, D’Atri S, Papa G, et al: Cisplatin increases sensitivity of human leukemic blasts to triazene compounds. J Chemother 7: 224-228, 1995[Medline]

19. D’Atri S, Graziani G, Lacal PM, et al: Attenuation of O6-methylguanine-DNA methyltransferase activity and mRNA levels by cisplatin and temozolomide in Jurkat cells. J Pharmacol Exp Ther 294: 664-671, 2000[Abstract/Free Full Text]

20. Baer JC, Freeman AA, Newlands ES, et al: Depletion of O6-alkylguanine-DNA alkyltransferase correlates with potentiation of temozolomide and CCNU toxicity in human tumour cells. Br J Cancer 67: 1299-1302, 1993[Medline]

21. Wedge SR, Newlands ES: O6-Benzylguanine enhances the sensitivity of a glioma xenograft with low O6-alkylguanine-DNA alkyltransferase activity to temozolomide and BCNU. Br J Cancer 73: 1049-1052, 1996[Medline]

Submitted January 7, 2002; accepted April 20, 2002.


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